Two molecules that possess identical chemical formulas with the same atoms bonded one to another but that differ in the manner that those atoms are arranged in space are referred to as stereoisomers. Stereoisomers that are mirror images of each other such that they are not superimposable one upon the other, because they have opposite configurations, are referred to as enantiomers. A mixture of equal parts of the two mirror image forms, or enantiomeric forms, is referred to as a racemic mixture.
Physiological activity has been shown to be closely related to the configuration of a molecule. For example, it is known that one enantiomeric form of adrenalin is over ten times more active in raising blood pressure than is the other form. Additionally, enzymes which catalyze chemical reactions in the body are frequently programmed to accept one enantiomeric form but not the other.
7-(Aminopyrrolidin-1-yl)naphthyridine carboxylic acids (Chu, U.S. Pat. No. 4,616,019, issued Oct. 7, 1986) and 7-(aminopyrrolidin-1-yl)quinolone carboxylic acids (Chu, U.S. Pat. No. 4,730,000, issued Mar. 8, 1988) are known to be antibacterial agents. A racemic mixture of 7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-o xo-1,8-naphthyridine-3-carboxylic acid has been shown to exhibit antibacterial properties. J. Med. Chem., 29, 2363 (1986).
A racemic mixture of 7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-o xo-1,8-naphthyridine-3-carboxylic acid is prepared by Reaction Scheme I as illustrated below: ##STR1##
In Reaction Scheme I, the oxime (2) is reduced with Raney nickel and hydrogen which results in a racemic mixture having equal parts of the two enantiomeric forms of the molecule (3). This racemic intermediate will subsequently result in the production of a racemic mixture of (A). However, only one enantiomeric form of (A) may possess biological activity. Further, one enantiomeric form of this molecule may be capable of producing an undesirable side effect while the other enantiomeric form may be the form that exhibits antibacterial properties. It is therefore desirable to provide a process for the preparation of a specific enantiomeric form of 7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-o xo-1,8-naphthyridine-3-carboxylic acid.
As will be discussed in greater detail below, one alternative is to provide an azide rather than the oxime (2), reduce the azide to an amine, acetylate the amine, and thereafter remove the benzyl group to obtain (4). The reduction of an azide to an amine is a process that is widely used in organic synthesis because of the high stereoselectivity associated with the preparation of the precursor azide. Accordingly, several methods and reagents are known to reduce an azide to an amine. For example, catalytic hydrogenation [Mungall, J. Org. Chem., 40, 1659 (1975); and Corey, Synthesis, 590 (1975)], or lithium aluminum hydride [Hedayatullah, Tetrahedron Lett., 2455 (1975); Brimacombe, Carbohydr. Res., 3, 318 (1967); Bose, J. Org. Chem., 27, 2925 (1962); and Boyer, J. Am. Chem., 73, 5865 (1951)]. Other processes include H.sub.2 S/pyridine/H.sub.2 O [Adachi, Synthesis, 45 (1977)]; transfer hydrogenation [Gartiser, Tetrahedron Lett., 24, 1609 (1984)]; Ph.sub.3 P/NH.sub.4 OH [Vaulter, Tetrahedron Lett., 24. 763 (1983)]; H.sub.2 /Lindlar catalyst [Corey, Synthesis, 590 (1975); Cr(II)/H+[Kirk, J. Chem. Soc. Chem. Commun., 64 (1970); and Kondo, Tetrahedron, 29, 1801 (1973)]; as well as Na.sub.2 S/Et.sub.3 N/MeOH [Belinka, J. Org. Chem., 44, 4712 (1979)]. Most recently, there have been reports of procedures using stannous chloride/MeOH [Maiti, Tetrahedron Lett., 27, 1423 (1986)]and NaBH.sub.4 /THF/MeOH [Soai, Synthesis, 48 (1986)]. Although many reagents have been proposed, none have proven completely satisfactory because they either lack chemoselectivity or require vigorous reaction conditions to achieve the desired reduction of the azide.